The TNF-like trimers BAFF and APRIL are recently identified molecules essential for B cell development and survival. Levels of BAFF and APRIL are elevated in autoimmune rheumatic diseases including SLE. Blockade of BAFF and APRIL delays the onset of SLE in murine models. We have preliminary observations that short term administration of the soluble BAFF and APRIL antagonist TACI-Ig together with the T cell costimulatory blocker CTLA41g can induce remission of late stage SLE in NZB/W F1 mice. This proposal will explore the mechanism of action of BAFF/APRIL blockade, both alone and in combination with CTLA41g, using soluble BAFF receptor fusion proteins that block BAFF or both BAFF and APRIL. The studies in Aim 1 will focus on how BAFF/APRIL blockade influences the effector B cells that mediate the inflammatory and non-inflammatory manifestations of SLE. The studies described in Aim 2A will focus on the effect of BAFF/APRIL blockade on the selection of autoreactive B cell subsets and on the autoreactive immunoglobulin gene repertoire. This will allow us to determine whether the decreased B cell survival that results from BAFF/APRIL blockade is linked to alterations in B cell selection. The studies described in Aim 2B will help us determine the immunosuppressive potential of the various forms of BAFF/APRIL blockade by analyzing primary and recall B cell responses to T independent and T dependent antigens. Finally, we have a unique opportunity, through collaboration with Human Genome Sciences, to study the mechanism of action of BAFF blockade in the first clinical trial of a BAFF blocker in human SLE.